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Repetitive

transcranial magnetic

stimulation for

treatment-resistant

major depression

Rapid assessment of other

technologies using the HTA

Core Model

®

for Rapid

Relative Effectiveness

Assessment

Decision Support Document No. 107

ISSN online: 1998-0469

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(3)

Repetitive

transcranial magnetic

stimulation for

treatment-resistant

major depression

Rapid assessment of other

technologies using the HTA

Core Model

®

for Rapid

Relative Effectiveness

Assessment

(4)

Project Team

Project leader: Dr. Katharina Hawlik, MSc Authors: Judit Erdös, MA

Nora Ibargoyen Roteta, MSc, PhD Iñaki Gutiérrez Ibarluzea Project Support

Systematic literature search: Tarquin Mittermayr, BA

External Review: Dr. Emmanuel Haffen, Professor of psychiatry, President of French Association of Biological Psychiatry and Neuropsychopharmacology, Head of laboratory of Neurosciences of the University of Franche-Comté, Head of the Clinical Investigation Centre of the University hospital of Besançon Dr. Dr. Jose Mª Vergara Ugarriza, Head of Neurophysiology of Miguel Servet University Hospital (Zaragoza), Aragon

Internal Review: Lilisbeth Perestelo Perez, MPsych, PhD Amado Rivero-Santana

Nancy Thiry, MSc Dr. Katharina Hawlik, MSc Proof reading: Michal Stanak, MA Factual accuracy check: Neurosoft, Russia

Mag&More GmbH, Germany Correspondence

Judit Erdös, MA. judit.erdos@hta.lbg.ac.at

This report should be referenced as follows:

Erdos J, Ibargoyen-Roteta N, Gutiérrez-Ibarluzea I. Repetitive transcranial magnetic stimulation for treatment-resistant major depression. Decision Support Document No. 107; 2017. Vienna: Ludwig Boltzmann Institute for Health Technology Assessment.

Conflict of interest

All authors and the reviewers involved in the production of this report have declared they have no conflicts of interest in relation to the technology assessed according to according to the EUnetHTA Declaration of interest and confidentiality undertaking of interest (DOICU) statement form.

Disclaimer

The external reviewers did not co-author the scientific report and do not necessarily all agree with its content. Only the LBI-HTA is responsible for errors or omissions that could persist. The final version and the policy recommendations are under the full responsibility of the LBI-HTA.

The HTA Core Model®, developed within EUnetHTA (www.eunethta.eu), has been utilised when producing the contents and/or structure of this work. The following version of the Model was used: HTA Core Model Application for Rapid Relative Effectiveness (REA) Assessments (4.2). Use of the HTA Core Model does not guarantee the accuracy, completeness, quality or usefulness of any information or service produced or provided by using the Model.

Commissioned by the Austrian Ministry of Health, this report systematically assessed the intervention described herein as decision support for the inclusion in the catalogue of benefits.

CONTENT INFORMATION Publisher:

Ludwig Boltzmann Gesellschaft GmbH Nußdorferstr. 64, 6 Stock, A-1090 Wien

http://hta.lbg.ac.at/page/imprint

Responsible for content:

Ludwig Boltzmann Institute for Health Technology Assessment (LBI-HTA) Garnisongasse 7/20, A-1090 Vienna

http://hta.lbg.ac.at/

Decision support documents of the LBI-HTA do not appear on a regular basis and serve to publicize the research results of the Ludwig Boltzmann Institute of Health Technology Assessments. Decision support documents of the LBI-HTA are only available to the public via the Internet at

http://eprints.hta.lbg.ac.at

Decision Support Document No.: 107 ISSN-online: 1998-0469

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LBI-HTA| 2017 3

Content

Summary

... 9

Zusammenfassung

... 15

1 Scope

... 21

1.1 PICO question ... 21

1.2 Inclusion criteria ... 21

2 Methods and evidence included

... 23

2.1 Research questions ... 23

2.2 Source of assessment elements ... 24

2.3 Search ... 24

2.4 Study selection ... 26

2.4.1 Selection of systematic reviews ... 26

2.4.2 Selection of primary studies ... 27

2.4.3 Selection of guidelines ... 28

2.5 Quality rating of studies ... 28

2.6 Statistical-analysis ... 29

2.7 Description of the evidence ... 30

3 Description and technical characteristics of technology (TEC)

... 33

3.1 Results ... 33

3.1.1 Features of the technology and comparators ... 33

4 Health problem and current use of the technology (CUR)

... 41

4.1 Results ... 41

4.1.1 Overview of the disease or health condition ... 41

4.1.2 Effects of the disease or health condition ... 42

4.1.3 Current clinical management of the disease or health condition ... 43

4.1.4 Target population ... 45

5 Clinical effectiveness (EFF)

... 47

5.1 Results ... 47

5.1.1 Included studies ... 47

5.1.2 Mortality ... 48

5.1.3 Morbidity ... 49

5.1.4 Health-related quality of life ... 57

5.1.5 Satisfaction ... 57

6 Safety (SAF)

... 59

6.1 Results ... 59

6.1.1 Included studies ... 59

6.1.2 Patient safety ... 59

7 Quality of evidence

... 63

8 Discussion

... 67

9 Recommendation

... 71

10 References

... 73

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Repetitive transcranial magnetic stimulation for treatment-resistant major depression

4 LBI-HTA | 2017

Appendix 1: Methods and description of the evidence used

... 79

Documentation of the Search Strategies ... 79

Search strategy for SRs ... 79

Search strategy for primary studies ... 82

Description of the evidence used ... 85

Guidelines for diagnosis and management ... 85

Main characteristics of systematic reviews assessed for eligibility ... 90

Evidence tables of individual studies included for clinical effectiveness and safety ... 98

List of ongoing and planned studies ... 118

Risk of bias tables ... 120

Applicability tables ... 121

Appendix 2: Regulatory and reimbursement status

... 122

Appendix 3: Checklist for potential ethical, organizational and legal aspects

... 126

Appendix 4: Diagnostic criteria according to DSM-IV-TR

... 127

Appendix 5: Safety guidelines

...

128

List of tables

Table 1-1: Inclusion criteria ... 21

Table 2-1: Main characteristics of the included systematic review for update ... 30

Table 2-2: Main characteristics of primary studies included in the update: rTMS vs sham... 31

Table 3-1: Features of the intervention ... 35

Table 6-1: Frequency of adverse events in comparative studies ... 61

Table 7-1: Evidence profile: efficacy and safety of rTMS vs sham for TRD ... 64

Table 7-2: Evidence profile: efficacy and safety of rTMS vs ECT for TRD ... 65

Table 9-1: Evidence based recommendations ... 71

Table A-1: Overview of guidelines: diagnosis and management of MDD ... 85

Table A-2: Overview of guidelines focusing on rTMS ... 87

Table A-3: Systematic reviews comparing rTMS with sham rTMS ... 90

Table A-4: Systematic reviews comparing rTMS with ECT ... 95

Table A-5: Characteristics of randomised controlled studies comparing rTMS with sham rTMS ... 98

Table A-6: Characteristics of randomised controlled studies comparing rTMS with ECT ... 114

Table A-7: List of Phase III and IV ongoing studies: sham controlled rTMS trials ... 118

Table A-8: List of Phase III and IV ongoing studies with rTMS compared to other than sham ... 119

Table A-9: Risk of bias – study level (RCTs) ... 120

Table A-10: Summary table characterising the applicability of a body of studies ... 121

Table A-11: Regulatory status ... 122

Table A-12: Summary of reimbursement recommendations in European countries for the technology... 124

Table A-13: Summary of recommendations in European countries for the technology

in the indication under assessment ... 125

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Content

LBI-HTA | 2017

5

List of figures

Figure 2-1: Flow chart for selection of systematic reviews ... 26

Figure 2-2: Flow chart for selection of primary studies ... 27

Figure 3-1: Mechanism of action of TMS ... 34

Figure 4-1: Thase-Rush Treatment-Resistant Depression (TRD) Staging Method ... 43

Figure 5-1: Weighted mean difference: rTMS vs sham ... 49

Figure 5-2: Standardized mean difference: rTMS vs sham ... 50

Figure 5-3: Weighted mean difference: rTMS vs ECT ... 51

Figure 5-4: Standardized mean different: rTMS vs ECT ... 51

Figure 5-5: Remission rate at the end of treatment: rTMs vs sham ... 52

Figure 5-6: Risk difference for remission rate: rTMS vs sham ... 53

Figure 5-7: Response rate at the end of treatment: rTMS vs sham ... 54

Figure 5-8: Risk difference for response rate: rTMS vs sham ... 54

Figure 5-9: Remission rate: rTMS vs ECT ... 55

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Repetitive transcranial magnetic stimulation for treatment-resistant major depression

6 LBI-HTA | 2017

List of abbreviations

ACROBAT-NRSi ... A Cochrane Risk Of Bias Assessment Tool

for Non-Randomized Studies of Interventions

ADE ... Adverse device effect

AE ... Adverse event

AGREE II ... Advancing guideline development reporting and evaluation in healthcare

AMSTAR ... A Measurement Tool to Assess Systematic Reviews

AOTMiT ... Agencja Oceny Technologii Medycznych i Taryfikacji/

Agency for Health Technology Assessment and pricing

APA ... American Psychiatric Association

aTMS ... Accelerated repetitive transcranial magnetic stimulation

AVALIA-t ... Galician Agency for Health Technology Assessment

B ... Bilateral

BDI ... Beck Depression Inventory

B-rTMS ... Bilateral repetitive transcranial magnetic stimulation

C ... Control

CANMAT ... Canadian Network for Mood and Anxiety Treatments

CBR ... Consensus based recommendation

CE mark ... Conformité Européene

CHIF ... Croatian Health Insurance Fund

CI ... Confidence interval

CPG ... Clinical practice guideline

CRD ... Centre for Research and Dissemination

CST ... Color Stroop Test

DBS ... Deep brain stimulation

DGPPN ... Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik

und Nervenheilkunde/German Association for Psychiatry and Psychotherapy

DLPFC ... Dorsolateral prefrontal cortex

DRG ... Diagnosis-related group

DSM IV-TR ... Diagnostic and statistical manual of mental disorders IV text revision

DTMS ... Deep transcranial magnetic stimulation

EBR ... Evidence-based recommendations

ECT ... Electroconvulsive therapy

EEG ... Electromyography

ETH ... Ethical

EUnetHTA ... European Network of Health Technology Assessment

FDA... Food and Drug Administration

fMRI ... Functional magnetic resonance imaging

FU ... Follow-up

G-BA... Gemeinsamer Bundesausschuss

GRADE ... Grading of Recommendations Assessment, Development and Evaluation

HAS ... French National Authority for Health

H-coil ... Hesed-coil

HDRS/HAMD ... Hamilton Depression Rating Scale

HF ... High-frequency

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Content

LBI-HTA | 2017

7

HQO ... Health Quality Ontario

HTA ... Health Technology Assessment

Hz ... Hertz

I ... Intervention

ICD ... International Classification of Diseases

ICTRP ... International Clinical Trials Registry Platform

IFCN ... International Federation of Clinical Neurophysiology

INFARMED ... National Authority of Medicines and Health Products

LBI-HTA ... Ludwig Boltzmann Institute for Health Technology Assessment

LEG ... Legal

LF ... Low-frequency

MA ... Meta-analysis

MADRS ... Montgomery-Asberg Depression Rating Scale

MAOB ... Monoamine oxidase B

MAOI ... Monoamine oxidase inhibitors

MDD ... Major depressive disorder

MDE ... Major depressive episode

MeSH ... Medical Subject Headings

MMSE ... Mini-Mental State Examination

mo ... month

MST ... Magnetic seizure therapy

MT ... Motor threshold

n ... number

N/A ... not available

NAMI ... National Alliance on Mental Illness

NARSAD ... National Alliance for Research on Schizophrenia and Depression

NCCHTA ... National Coordinating Centre for Health Technology Assessment

NHMRC ... National Health and Medical Research Council

NHS... National Health Service

NICE ... National Institute for Health and Clinical Excellence

NIHM ... National Institute of Mental Health

NIJZ ... National Institute of Public Health Slovenia

NIRS ... Near Infrared Spectroscopy

NOS ... Not Otherwise Specified

OGYEI ... Országos Gyógyszerészeti és Élelmezés-egészségügyi Intézet/

National Institute of Pharmacy and Health Products

ORG ... Organizational

OSTEBA ... Basque Office for Health Technology Assessment

PCP ... Phencyclidine

PET ... Positron emission tomography

pts ... patients

QIDS ... Quick Inventory of Depressive Symptomatology

Q-LES-Q ... Quality of Life Enjoyment and Satisfaction Questionnaire

QoL ... Quality of life

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Repetitive transcranial magnetic stimulation for treatment-resistant major depression

8 LBI-HTA | 2017

RCT ... Randomized controlled trial

REA ... Relative Effectiveness Assessment

RedAETS ... Red Española de Agencias de Evaluación de Tecnologías Sanitarias

RMT ... Resting motor threshold

RR ... Relative risk

R-rTMS ... Right-side repetitive transcranial magnetic stimulation

rTMS ... Repetitive transcranial magnetic stimulation

SADE ... Serious adverse device effect

SCID ... Structured Clinical Interview for DSM-IV

SD ... Standard deviation

SESCS ... Evaluation Unit of the Canary Islands Health Service

SF 36 PF ... Short Form (36) Health Survey Physical Functioning

SF-36 ... Study-36 Item Short Form

SIGH-SAD ... Structured Interview Guide for the Hamilton Depression Rating Scale

SIGN ... Scottish Intercollegiate Guidelines Network

SMD ... Standardized mean difference

SNRI ... Serotonin–norepinephrine reuptake inhibitors

SOC ... Social

SR ... Systematic review

SSES ... Suicide severity rating scale

SSRI ... Selective serotonin reuptake inhibitors

STAI ... State-Trait Anxiety Inventory

STAR*D ... Sequenced Treatment Alternatives to Relieve Depression

sTMS ... Synchronized transcranial magnetic stimulation

TBS ... Theta Burst Stimulation

TCA ... Tricyclic antidepressants

TDCS ... Transcranial direct current stimulation

TGA ... Therapeutic Goods Administration

TMS ... Transcranial magnetic stimulation

TMT ... Trail Making Test

TRD ... Treatment-resistant depression

UK ... United Kingdom

UMDNS ... Universal Medical Device Nomenclature System

VFT ... Verbal Fluency Test

VNS ... Vagus nerve stimulation

vs ... versus

w ... week

WCST ... Wisconsin Card Sorting Test

WHO ... World Health Organization

WSFBP ... World Federation of Societies of Biological Psychiatry

yrs ... years

(11)

LBI-HTA| 2017 9

Summary

Scope

The scope can be found here:

Scope

.

The aim of this report was to assess the effectiveness and safety of repetitive

transcranial magnetic stimulation (rTMS) in treatment-resistant depression

(TRD).

Introduction

Health problem

The target condition in the scope of the assessment is treatment-resistant

major depressive disorder (TRD), which often refers to major depressive

dis-order (MDD) that does not respond satisfactorily to at least two trials of

an-tidepressant monotherapy. However, the definition has not been standardized

yet. Defining treatment resistant depression is also complicated due to the

lack of consensus in describing acute antidepressant responses. In many

stud-ies, response is classified as ≥ 50 percent improvement from baseline on the

depression rating scale. Remission is defined as a depression rating scale score

less than or equal to a specific cut-off that defines the normal range (score on

the HRSD-17 or on the MASD ≤ 7) [1] (A0002).

The prevalence of unipolar TRD is not clear due to the lack of

international-ly acknowledged and standardized definition. However, there are reasonable

estimates available. If response is used as outcome, according to the

defini-tion of response, the prevalence rate for Stage 2 TRD (failure to achieve

re-sponse after two courses of adequate treatment) is estimated to be 15-35% [5,

6, 44] (A0023).

MDD is currently diagnosed by using the Diagnostic Criteria for Major

De-pressive Disorder and DeDe-pressive Episodes (DSM-IV-TR) (details in

Appen-dix 4). Because of differences in treatment, the diagnosis of unipolar MDD

should be confirmed and other diagnosis, such as bipolar depression or

dys-thymic disorder, ruled out. The treatment history of patients who may be

treat-ment resistant is usually assessed through a clinical interview as well as a

re-view of the medical record [1] (A0024).

Description of technology and comparators

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive

neu-rostimulation and neuromodulation technique, which is delivered as a series

of pulses i.e. a train. The most typical technical parameters of rTMS are the

frequency (high-frequency: stimulation delivered >1 pulse per second, but

generally ≥ 5 Hz is applied as HF [5, 7], or low-frequency: stimulation

de-livered at ≤ 1 pulse per second), intensity (expressed as a percentage of the

resting motor threshold, generally set at 100-120%), train duration, intertrain

interval, number of trains per session, and number of pulses per session [7, 8].

There are various treatment protocols, but the FDA-based standard

parame-ters are most widely used and for the acute treatment they include: 10

mag-netic pulses per second (Hz), 3000 pulses per session, 100 to 120 percent of

motor threshold and train duration of 4 s with intertrain interval of 26 s [9].

However, the stimulation parameters required to optimize the efficacy of

rTMS treatment are not well known.

aim

target population:

patients with TRD

unclear prevalence

diagnosis:

DSM-IV-TR criteria

rTMS: non-invasive

neurostimulation

Technical parameters:

frequency

intensity

train duration

intertrain interval

number of trains

per session

number of pulses

per session

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Repetitive transcranial magnetic stimulation for treatment-resistant major depression

10 LBI-HTA | 2017

The use of the rTMS is prohibited for patients with metal implants in the

head area, implanted medical devices during pregnancy, increased

intracra-nial pressure, a history of epileptic seizures, increased cerebral susceptibility

to epileptic seizures through medication and unstable general medical

disor-ders [7, 8, 10] (A0001).

rTMS is indicated for patients with unipolar major depression who have failed

to achieve satisfactory improvement from prior antidepressant medication in

the current episode (A0020). The claimed benefit of rTMS is that it is

non-in-vasive, the patient remains awake and alert throughout the process, no

post-session recovery is needed, hence the patient can resume normal activities

immediately and no cognitive side-effects have been reported with rTMS.

Comparators

Sham stimulation

is delivered with a sham coil.

Electroconvulsive therapy

(ECT) involves the induction of a seizure by the

ap-plication of electrical current to the brain. It is delivered under general

an-aesthesia and application of a muscle relaxant. Treatment parameters include

electrode position, electrical intensity, pulse width and duration [11]. ECT is

a complex intervention and its efficacy and safety are affected by a number

of parameters including the placement of electrodes, dosage and waveform of

the electrical stimulus, and the frequency with which ECT is administered

[12]. As regards to mortality, ECT is a safe procedure with a very low mortality

rate (1 death per 73,440 treatments) [11] (A0001). However, cognitive effects

including transient disorientation when recovering from ECT sessions,

retro-grade and anteroretro-grade amnesia, mild, short-term impairment in memory and

other cognitive domains during and after treatment with ECT might occur.

[4, 11] (B0002).

Methods

The systematic literature search and analysis of the studies was performed in

two phases: secondary studies (i.e. HTA reports and systematic reviews/SRs)

were screened as a first step and evaluated on the basis of their scope,

inclu-sion and excluinclu-sion criteria, and quality. The AMSTAR tool was used for

quali-ty assessment of SRs, and as a result, the Health Qualiquali-ty Ontario (HQO)

re-port [13] was selected for update.

As a second step, to identify further, more recent, primary studies fulfilling

the inclusion criteria of the present assessment, a literature search for

ran-domized controlled trials (RCTs) published since the literature search of the

chosen HQO report [13] was performed. 2 studies [14, 15] were selected that

fulfilled our inclusion criteria and included within the present assessment.

The 2 studies compare HF-rTMS to the left DLPFC with sham. No studies

were found that compared active stimulation with ECT. The Cochrane risk

of bias assessment approach was used to assess the quality of RCTs. For the

assessment of the strength of evidence, the Grading of Recommendations,

Assessment, Development and Evaluation approach was used.

Clinical effectiveness

The critical endpoints in assessing clinical effectiveness were response and

remission rates. The mean difference in depression scores was considered

im-portant, but not critical endpoint.

contraindications

benefits: non-invasive,

no cognitive side-effects,

no general anaesthesia

needed, no post-session

recovery needed

comparators: sham

stimulation

(with a sham coil) …

… and ECT

(neuromodulation

under general

anaesthesia,

induction of a seizure

to the brain)

2-step systematic

literature search:

1. SRs and HTAs

2. RCTs

HQO report selected

for update

Inclusion of additional

2 RCTs

Cochrane risk of bias

tool to assess quality

GRADE approach to

assess the strength of

evidence

critical endpoints:

response and remission

(13)

Summary

LBI-HTA | 2017

11

Safety

The critical endpoint in assessing safety was cognitive impairment, whereas

the number of seizures was considered important endpoint.

Results

Available evidence

rTMS vs sham

23 studies met the inclusion criteria in the HQO report. We found two

addi-tional RCTs [14, 15] that are included in the present analysis. One of them

[15] is the 6 month follow-up of a study included in the HQO report [16]. A

total of 1180 patients were analysed in the studies, 615 in the rTMS arm and

565 in the sham arm.

The inclusion criteria of the studies varied as follows:

Baseline values on HDRS-17

In 11 studies: >25 (severe depression)

In 6 studies: 19-24 (moderate depression)

TRD definition

In 16 studies: two or more failed antidepressant trials

In 9 studies: one or more failed antidepressant trial

rTMS as add-on or monotherapy

In 17 studies: add-on therapy

In 8 studies: monotherapy

The stimulation parameters varied: the frequency ranged from 5 to 20 Hz,

the intensity from 80 to 120% of patients’ MT, the number of trains per

ses-sion from 15 to 75, the train duration from 2 to 10 seconds (s), the intertrain

interval from 22 to 58 s, the number of pulses per session from 800 to 3,000,

and the total number of pulses during rTMS treatment from 8,000 to 90,000.

All studies used the figure 8 coil.

rTMS vs ECT

The HQO report included six studies that compared rTMS with ECT. Most

of the studies were conducted in the early 2000s. The total number of patients

was 266, 133 in each arm. Two of the studies reported 6 month follow-up

da-ta as well [17, 18].

The inclusion criteria of the studies varied as follows:

Baseline values on HDRS-17

In the rTMS group: 24-26

In the ECT group: 25-28

TRD definition

In 2 studies: two or more failed antidepressant trials

In 1 study: one or more failed antidepressant trial

In 2 studies the number of failed antidepressant trials was not

re-ported, only the number of failed ECT trials

In 1 study only the number of failed antidepressants in the

cur-rent episode was reported

critical endpoint:

cognitive impairment

25 included studies with

1180 patients

inclusion criteria

varying stimulation

parameters

6 included studies with

266 patients

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Repetitive transcranial magnetic stimulation for treatment-resistant major depression

12 LBI-HTA | 2017

rTMS as add-on or monotherapy

In 2 studies: add-on therapy

In 2 studies: monotherapy

In 2 studies: only lorazepam or clonazepam were allowed

The characteristics of the intervention varied also, one study used 20 Hz

fre-quency stimulation, four studies used 10 Hz and one study did not report on

the frequency used. The intensity of the stimulation ranged from 90 to 110%

of the MT, the number of trains from 20 to 30-35, the train duration from 2

to 10 s, the intertrain interval from 20 to 55 s, the pulses per session from 408

to 2500 and the number of sessions from 10 to 20. Hence the total number of

pulses delivered also ranged from 4,080 to 50,000. All studies reported that

they used a figure 8 coil.

Clinical effectiveness

rTMS vs sham

The pooled risk ratio for response rate across 19 studies was 1.82 (95% CI

1.18-2.82; p=.0068). There was a moderate degree of heterogeneity among studies

(I

2

=50%, p=.01). This pooled estimate suggests that patients may be twice

more likely to experience treatment response with rTMS than with sham.

The pooled risk ratio for remission rate across 12 studies was 2.16 (95% CI

1.42-3.29; p=.0003). This pooled estimate suggests that patients may be twice

more likely to experience remission with rTMS than with sham. No

hetero-geneity was observed among the studies (I

2

=0.0%; p=.7164).

On average, rTMS reduced depression scores by about 2.31 points more than

sham (95% CI 1.19-3.43; p<.001), which is below the mean value that was

deemed a priori clinically important (threshold of 3.5 points).

There was a statistically significant improvement favouring rTMS on the

gen-eral health and mental health SF-36 subscales at 4- and 6-week follow-up.

Statistically significant improvement favouring rTMS was also seen in the

Q-LES-Q total score at 4-and 6-week follow-up [15] (D0012, D0013).

rTMS vs ECT

The pooled risk ratio for response at the end of treatment was 1.72 (95% CI

0.95-3.11, p=.072) favouring ECT. There was a high degree of heterogeneity

among studies (I

2

=60.6%, p=.079). While the effect is not statistically

signif-icant, this pooled estimate would suggest a higher response with ECT than

with rTMS (D0006).

The pooled risk ratio for remission was 1.44 (95% CI 0.64-3.23, p=.375) at

the end of treatment, favouring ECT, however, these results are not

signifi-cant. There was a high degree of heterogeneity among studies (I

2

=69.1%,

p=.039).

The weighted mean difference of depression scores from baseline to the end

of treatment was -5.97 points (95% CI -11.00 to-0.94, p=.020) in favour of ECT,

which is higher than the mean value that was defined a priori as clinically

important. The degree of heterogeneity among studies was high (I2=72.2%,

p=.013) (D0005).

One study [19] reported data on suicide scores or suicidal ideations. The

su-icide score decreased from 1.5 (0.8) to 1.2 (0.9) as measured by BDI and from

1.9 (1.3) to 1.4 (1.2) as measured by HDRS in the rTMS group. In the ECT

varying stimulation

parameters

RR for response:

1.82 favouring rTMS

RR for remission:

2.16 favouring rTMS

MD 2.31 points

favouring rTMS

significant improvement

favouring rTMS in

general health, mental

health, and Q-LES-Q

RR for response:

1.72 favouring ECT,

but statistically not

significant

RR for remission:

1.44 favouring ECT,

but statistically not

significant

MD 5.97 points

favouring ECT

decrease in suicide

scores greater in the

ECT group

(15)

Summary

LBI-HTA | 2017

13

group the decrease was significantly greater: from baseline 1.4 (1.0) to 0.5

(0.7) as measured by BDI and 2.3 (1.1) to 0.3 (0.5) as measured by HDRS

(p<.001). The results suggest that ECT decreases suicidal scores more than

rTMS.

Safety

rTMS vs sham

The most common side-effect presented in the studies was headache. The rate

of headache ranged from 0 to 60% in the rTMS group and from 0 to 50% in

the sham group. Seizures did not occur in any of the studies and transient

impairment of working memory occurred in five patients (16.7%) in the rTMS

group and in one patient (4.3%) in the sham group (C0008).

rTMS vs ECT

No serious safety concerns were identified. The most common side-effect

was headache in rTMS-treated patients. No adverse events occurred in

ECT-treated patients (C0008).

Upcoming evidence

There are four ongoing studies on rTMS compared to sham stimulation, no

ongoing studies comparing rTMS with ECT.

Reimbursement

The technology is not reimbursed in the majority of the countries for which

we have information available (A0021). The reason for its non-inclusion in

the benefit catalogue is either that it has not been assessed or that the

evi-dence is insufficient to issue a recommendation.

Discussion

The overall quality of the body of evidence is very low for both sham and

ECT comparison studies.

The methodological limitations of the studies included in this assessment are

likely to influence the robustness of our findings. These limitations include

variable study parameters (rTMS treatment protocols, the definition of

re-mission, the level of treatment resistance, and if rTMS was used as mono- or

add-on therapy), risk of bias (high risk of bias in the blinding domain in ECT

controlled studies), small sample sizes (in both the sham and ECT controlled

trials).

Ideally, outcomes such as quality of life and function would be primary

out-comes that determine the impact of the intervention, but this was not

re-ported in the included studies, except for one. A major limitation in the

out-comes is that they are not measuring directly the improvement in the

pa-tients’ quality of life and that there is only short-term data available. Patient

satisfaction was also not measured by any dedicated tool.

most common

side-effect: headache

no serious adverse

events

4 ongoing studies

rTMS vs sham

currently not

reimbursed

very low quality of

the body of evidence

methodological

limitations

QoL outcomes and

patient satisfaction

neglected in the studies

(16)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

14 LBI-HTA | 2017

Conclusion

The body of evidence indicates that rTMS is generally safe and well-tolerated.

rTMS had a small short-term effect for improving depression in comparison

with sham, but follow-up studies did not show that the small effect will

con-tinue for longer periods. It remains unresolved if rTMS is as effective as

ECT, since no significant differences in remission and response rates where

found, and studies showed high heterogeneity at a low total sample size.

How-ever, rTMS patients had less, and not clinically relevant decreases in

depres-sion scores as compared to ECT patients.

Due to the low quality of evidence, new study results would potentially

in-fluence the effect estimate considerably. Additional research is needed to

support the finidings with high-quality evidence.

rTMS is safe and

well-tolerated, more

effective than sham,

unclear effectiveness

compared to ECT

further research

needed

(17)

Zusammenfassung

LBI-HTA | 2017

15

Zusammenfassung

Einleitung

Indikation und therapeutisches Ziel

Der Fokus dieses Berichts liegt in der Bewertung der transkraniellen

Mag-netstimulation zur Behandlung therapieresistenter Depression (TRD). Der

Bericht ging der Frage nach, ob repetitive transkranielle Magnetstimulation

(rTMS) im Vergleich zu einer Scheinintervention und im Vergleich zur

Stan-dardintervention der Elektrokonvulsionstherapie gleich wirksam bzw.

wirk-samer und gleich sicher, bzw. sicherer ist bei der Behandlung der TRD.

Unter TRD wird eine schwere Form der Depression verstanden (im

Engli-schen

Major Depression Disorder

, MDD), bei nach mindestens zwei Versuchen

verschiedener Antidepressiver Therapie (AD) sich keine Verbesserung

ein-stellt. Eine allgemeingültige Definition gibt es zurzeit jedoch noch nicht. Die

genaue Definition ab wann eine schwere Depression therapieresistent ist, ist

auch deshalb schwierig, da es keine Einigung gibt was als Therapieansprechen

gilt. In vielen Studien wird Therapieansprechen als eine mehr als 50

prozen-tige Verbesserung auf der Depression Skala eingestuft [1].

MDD wird derzeit mit den

Diagnostic Criteria for Major Depressive Disorder

and Depressive Episods

(DSM-IV-TR) diagnostiziert (Details in Appendix 4).

Alternative Verdachtsdiagnosen, wie bipolare Depression oder dysthymische

Störung, sollten aufgrund der unterschiedlichen Behandlungsmöglichkeiten

ausgeschlossen werden. Therapieresistente PatientInnen werden durch

Anam-nese und Krankengeschichte identifiziert.

Die Prävalenz der unipolaren TRD ist aufgrund der fehlenden international

anerkannter Definition nicht klar. Schätzungen zufolge sprechen 30-40 %

oder 50 % der PatientInnen – abhängig von der gewählten Definition des

The-rapieansprechens – nicht auf eine AD-Therapie an [3, 5, 44]. In Österreich

werden 120.000 bis 140.000 Patienten pro Jahr mit Depressionen

diagnosti-ziert, von denen nur 24.000 bis 36.000 ausreichend behandelt und Remission

erreicht wird [48]. Von den restlichen 84.000 bis 116.000 Patienten, werden

geschätzte 10-15 % (8.400 bis 17.400 Personen) nicht auf eine Therapie

an-sprechen.

Beschreibung der Technologie

Die repetitive transkranielle magnetische Stimulation (rTMS) ist eine

nicht-invasive Neurostimulation, die als eine Reihe Einzelimpulsen über eine

Mag-netspule auf den Kortex übertragen wird. Die typischsten technischen Daten

eines Einzelstimulus sind die Frequenzen (Hochfrequenz-Stimulation >1Hz

[5, 7] oder Niederfrequenz-Stimulation bei ≤ 1 Hz), Intensität,

Stimulations-dauer, Intervall zwischen den einzelnen Stimuli, und die Anzahl der Stimuli

pro Sitzung [7, 8].

Es gibt verschiedene Behandlungsprotokolle, wobei die FDA-basierten

Stan-dardparameter am weitesten verbreitet sind und für diesen Bericht

berück-sichtigt wurden: 10 magnetische Impulse pro Sekunde (Hz), 3.000 Impulse

pro Sitzung, 100 bis 120 % Intensität, Stimulationsdauer von 4 s mit

stimula-tionsfreiem Intervall von 26 s [9]. Die optimalen Einstellungen für die

Wirk-samkeit der rTMS sind allerdings nicht belegt.

Fragestellung

Definition TRD:

schwere Depression,

keine Verbesserung

durch verschiedene

AD Therapie

MDD = schwere

Depression,

nach DSM-IV TR

diagnostiziert

Prävalenz: nicht klar,

geschätzt: bis zu 50 %

der PatientInnen kein

Therapieansprechen

auf AD-Therapie

in Österreich:

140.000 PatientInnen

mit Depression,

circa 15 % TRD

rTMS: nicht-invasive

kranielle Stimulation

verschiedene Arten und

Intensitäten (niedrig

und hochfrequent

rTMS)

unterschiedliche

Behandlungsprotokolle,

meist:

FDA-Standardparameter

(18)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

16 LBI-HTA | 2017

rTMS ist für PatientInnen mit unipolarer, schwerer Depression (MDD)

in-diziert, die keine zufriedenstellende Verbesserung durch vorangegangene AD

Therapie hatten. Der erwartete Vorteil der rTMS gegenüber der Vergleich

Intervention der elektrokonvulsiven Therapie (ECT) ist die geringe

Invasi-vität, die ambulante Anwendung ohne Notwendigkeit einer Anästhesie und

Aufwachphase. Die PatientInnen können ihrer Tätigkeit im Anschluss der

Intervention ohne Einschränkungen nachgehen. Es wurden des Weiteren

kei-ne kognitiven Einschränkungen bei der Behandlung mit rTMS berichtet. Bei

ECT Sitzungen hingegen, können vorübergehende kognitive

Einschränkun-gen vorkommen, und umfassen Desorientierung beim Aufwachen, Amnesie,

Beeinträchtigung des Gedächtnisses während und nach der Behandlung mit

ECT. Allerdings sind diese Nebenwirkungen üblicherweise nur

vorüberge-hend mit Wiederherstellung der vollen kognitiven Funktionen innerhalb von

Wochen oder Monaten [4, 11].

Kontraindikationen für die Anwendung von rTMS sind PatientInnen mit

Me-tallimplantaten im Kopfbereich, implantierte Medizinprodukte

(Cochlea-Im-plantat, Herzschrittmacher, etc.), Schwangerschaft, erhöhter intrakranieller

Druck, Epilepsie bzw. erhöhte zerebrale Anfälligkeit für epileptische

Anfäl-le und allgemeine instabiAnfäl-le Komorbiditäten [7, 8, 10].

Methoden

Zur Beantwortung der Forschungsfrage wurde eine systematische

Literatur-suche und -analyse in zwei Phasen durchgeführt: als erster Schritt wurden

Sekundärstudien (z. B. HTA-Berichte und systematische Reviews/SRs)

an-hand ihrer Qualität, und ihrer Einschluss- und Ausschlusskriterien

bewer-tet. Zur Qualitätsbewertung der SRs wurde AMSTAR-Tool verwendet. Aus

insgesamt 20 vorliegenden SR wurde der Health Quality Ontario (HQO

Be-richt) [13] ausgewählt. In einem zweiten Schritt wurde eine ergänzende Suche

nach Primärstudien durchgeführt, die seit der Literatursuche des gewählten

HQO-Berichts [13] veröffentlicht wurden, und führte zum Einschluss zweier

randomisierter, kontrollierter Studien (RCT) [14, 15]. Die Studien verglichen

HF-rTMS mit der linken DLPFC mit einer Scheinintervention. Es wurden

keine weiteren Primärstudien gefunden, die rTMS mit ECT verglichen

ha-ben.

Klinische Wirksamkeit

Die Endpunkte Therapieansprechrate und Remissionsrate wurden für die

Beurteilung der Wirksamkeit als entscheidend definiert. Des Weiteren

wur-de eine durchschnittliche Verbesserung auf wur-der Depressionsskala (HDRS) als

wichtiger, jedoch nicht entscheidender Endpunkt herangezogen.

Sicherheit

Der entscheidende Endpunkt für die Beurteilung der Sicherheit war die

kog-nitive Einschränkung; wobei die Anzahl der Anfälle als wichtiger Endpunkt

eingestuft wurde.

rTMS indiziert für

PatientInnen mit MDD

ohne Verbesserung

bei AD Therapie

rTMS: wenig invasiv,

ambulant,

keine kognitiven

Einschränkungen

nach Behandlung

diverse

Kontraindikationen

entscheidende

Endpunkte Wirksamkeit

entscheidende

Entpunkte Sicherheit

(19)

Zusammenfassung

LBI-HTA | 2017

17

Ergebnisse

Verfügbare Evidenz

rTMS vs sham

Im HQO Bericht erfüllten 23 Studien die Einschlusskriterien, die durch zwei

zusätzliche RCTs aus der Primär Suche ergänzt wurden [14, 15]. Eines der

beiden RCTs [15] ist eine 6-Monats-Follow-up Studie einer im HQO-Bericht

bereits enthaltenen Studie [16]. Insgesamt wurden 1.180 Patienten in den

Stu-dien analysiert, 615 im aktiven rTMS-Arm und 565 im Scheinarm.

Die Einschlusskriterien der Studien unterschieden sich folgendermaßen:

Ausgangwerte auf der HDRS-17 Skala:

11 Studien: >25 HDRS-17 (schwere Depression)

14 Studien: 19 bis 24 (moderate Depression)

AD- Einnahme:

16 Studien: vorangegangener AD-Therapieversuch

mit zwei oder mehr AD

9 Studien: vorangegangener AD-Therapieversuch

mit einem oder mehr AD

17 Studien: rTMS unter AD- Therapie

8 Studien: keine AD Therapie während rTMS

Stimulationsparameter:

Frequenz (5 bis 20 Hz), Intensität (80 bis 120 %), Anzahl der

Sti-mulationen pro Sitzung (15 bis 75), die Stimulationsdauer (2 bis

10 Sekunden), Zwischenintervall (22 bis 58 Sekunden), Anzahl der

Impulse pro Sitzung von (800 bis 3.000) Gesamtzahl der Impulse

während der rTMS-Behandlung (8.000 bis 90.000).

Alle Studien verwendeten die

Figur 8

Spulen.

rTMS vs ECT

Der HQO-Bericht enthielt sechs Studien, die rTMS mit ECT verglichen. Die

meisten Studien wurden in den frühen 2000er Jahren durchgeführt. Die

Ge-samtzahl der Patienten betrug 266, 133 in jedem Arm.

Die Einschlusskriterien der Studien unterschieden sich folgendermaßen:

Ausgangwerte auf der HDRS-17 Skala:

24 bis 26 in der rTMS-Gruppe

25 bis 28 in der ECT-Gruppe

AD- Einnahme:

2 Studien: vorangegangener AD-Therapieversuch

mit zwei oder mehr AD

1 Studie: vorangegangener AD-Therapieversuch mit einem oder

mehr AD, bzw. 1 Studie berichtete AD-Therapieversuche in der

derzeitigen Episode

2 Studien: Einschluss von PatientInnen mit vorangegangener

ECT Therapie (keine Information zur AD Therapie)

2 Studien: rTMS bzw. ECT unter AD Therapie

2 Studien: medikamentenfrei

2 Studien: Therapie mit Lorazepam oder Clonazepam

verfügbare Evidenz:

SR mit 23 Studien,

2 RCTs

unterschiedliche

Einschlusskriterien der

verschiedenen Studien

in Bezug auf

Ausgangswerte,

AD-Einnahme und

Stimulationsparameter

verfügbare Evidenz:

SR mit 6 Studien,

266 PatientInnen,

133 pro Arm

unterschiedliche

Einschlusskriterien der

verschiedenen Studien

in Bezug auf

Ausgangswerte,

AD-Einnahme und

Stimulationsparameter

(20)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

18 LBI-HTA | 2017

Stimulationsparameter:

Frequenz (10Hz bzw 20 Hz), Intensität (90 bis 110 %), die Anzahl

der Stimulationen (20 bis 30-35), die Stimulationsdauer (2 bis 10 s),

Zwischeninterval (20 bis 55 s), die Impulse pro Sitzung (408 bis

2.500), Anzahl der Sitzungen (10 bis 20). Gesamtzahl der

geliefer-ten Impulse (4.080 bis 50.000).

Alle Studien verwendeten die

Figur 8

Spulen.

Klinische Wirksamkeit

rTMS vs sham

Im Durchschnitt verringerte rTMS die Punktezahl auf der Depressionsskala

um etwa 2.31 Punkte mehr als die Scheinintervention (95 % CI 1.19-3.43, p

<.001). Dies liegt allerding unter dem klinisch relevanten Schwellenwert von

3.5 Punkten.

Das gepoolte Risikoverhältnis für die Remissionsrate über 12 Studien betrug

2.16 (95 % CI 1.42-3.29, p = 0.0003). Das gepoolte Risiko-Verhältnis für die

Ansprechrate über 19 Studien betrug 1.82 (95 % CI 1.18-2.82, p = 0.0068).

In Bezug auf allgemeine und psychische Gesundheit, gemessen mit dem

SF-36 score, berichtete ein RCT [15] statistisch signifikanten Verbesserungen in

der rTMS Gruppe. Auch in Hinblick auf QoL fand die Studie statistisch

sig-nifikante Verbesserung in der rTMS Gruppe, gemessen mit dem

Q-LES-Q-Score.

rTMS vs ECT

Die gewichtete mittlere Differenz der Depressionswerte von der Baseline bis

zum Ende der Behandlung betrug -5.97 Punkte (95 % CI -11.00 – (-0.94), p =

0.020) zugunsten von ECT, und damit höher der klinisch relevante

Schwel-lenwert.

Das gepoolte Risikoverhältnis für die Remission betrug 1.44 (95 % CI

0.64-3.23, p = 0.375) am Ende der Behandlung zu Gunsten von ECT. Diese

Er-gebnisse sind allerdings nicht signifikant und die Studien wiesen ein hohes

Maß an Heterogenität auf (I

2

= 69.1 %, p = 0.039).

Das gepoolte Risikoverhältnis Therapieansprechrate betrug 1.72 (95 % CI

0.95-3.11, p = 0.72). Wiederum waren diese Ergebnisse nicht signifikant, mit

einem hohen Maß an Heterogenität der Studien (I

2

= 60.6 %, p = 0.079).

Die Selbstmordgedanken, gemessen sowohl mit BDI als auch HDRS Skala,

sanken signifikant stärker in der ECT Gruppe als in der rTMS Gruppe.

Sicherheit

rTMs vs sham

Die am häufigsten berichtete Nebenwirkung war Kopfschmerz. Die Rate der

Kopfschmerzen reichte von 0 bis 60 % in der rTMS-Gruppe und 0 bis 50 %

in der Scheingruppe. Krampfanfälle traten in keinen Studien auf, eine

tran-siente kognitive Beeinträchtigung trat bei fünf PatientInnen (16.7 %) in der

rTMS-Gruppe und einem Patienten (4.3 %) in der Scheingruppe ein.

rTMS vs ECT

Es wurden keine schwerwiegenden Nebenwirkungen berichtet. Bei

rTMS-PatientInnen waren Kopfschmerzen die häufigsten Nebenwirkungen,

ECT-PatientInnen berichten keine unerwünschten Ereignisse.

rTMS vs Sham

Verbesserung in der

Depressionsskala um

2,31 Punkte, klinisch

nicht relevant

Remissionsrate: RR 2.16

Ansprechrate: RR 1.82

zugunsten von rTMS

QoL: 1 RCT berichtete

signifikante

Verbesserungen

Verbesserung in der

Depressionsskala um

5,97 Punkte in

ECT Gruppe,

klinisch relevant

keine signifikanten

Unterschiede zw. rTMS

und ECT in Remissions-

und Ansprechraten

geringere

Selbstmord-gedanken bei ECT

keine schwerwiegenden

NW berichtet, häufigste

NW war Kopfschmerz

bei PatientInnen mit ECT

traten keine NW auf

(21)

Zusammenfassung

LBI-HTA | 2017

19

Laufende Studien

Es gibt vier laufende Studien zu rTMS im Vergleich zur Scheinstimulation,

aber keine laufenden Studien, die rTMS mit ECT vergleichen.

Kostenerstattung

Die Technologie wird in der Mehrheit der Länder, für die wir Informationen

zur Verfügung hatten, sowie in Österreich, nicht zurückerstattet.

Diskussion

Die Gesamtqualität des Beweismaterials ist sowohl für Schein- als auch für

ECT-Vergleichsstudien sehr gering.

Die methodischen Einschränkungen könnte die Empfehlung in Hinblick auf

die Robustheit der Wirksamkeitsergebnisse erheblich beeinflussen. Diese

Ein-schränkungen beinhalten variable Studienparameter

(rTMS-Behandlungspro-tokolle, die Definition der Remission, die Definition der TRD, Verwendung

als Mono- oder Add-On-Therapie), das Bias Risiko (ein hohes Risiko Bias dem

ECT-kontrollierte Studien auf Grund fehlender Verblindung), kleine

Patien-tInnen Fallzahlen (sowohl im Schein- als auch in der ECT-kontrollierten

Stu-die).

Lebensqualität und PatientInnen Zufriedenheit wären wünschenswerte

pri-mär Endpunkte für Studien an therapieresistenter Depression; diese wurden

jedoch nur von einer Studie berichtet. Des Weiteren fehlen Langzeitdaten zu

Wirkung von rTMS.

Empfehlung

Die Ergebnisse der Bewertung zeigen, dass rTMS im Allgemeinen sicher und

gut verträglich ist. rTMS hatte einen kurzfristigen Effekt auf die

Verbesse-rung der Depression im Vergleich zur Scheinintervention, der allerdings

kli-nisch nicht relevant sein könnte. Follow-up Studien konnten keinen

langan-haltenden Effekt von rTMS finden.

Die Wirksamkeit im Vergleich zu ECT zeigt einen Vorteil von ECT

gegen-über rTMS in Bezug auf die klinisch relevante Verbesserung auf der

Depres-sionsskala; jedoch gibt es keine signifikanten Unterschiede im Hinblick auf

Ansprechrate und Remissionsrate. Die Qualität der Studien ist sehr niedrig,

unter anderem bedingt durch die niedrige Fallzahl und hohe Heterogenität

der Studien.

Aufgrund dieser niedrigen Qualität der Evidenz könnten neue

Studiener-gebnisse die Effektschätzung erheblich beeinflussen. Weitere Studien, die

Langzeitdaten zu rTMS untersuchen, sind notwendig, um die tatsächliche

Wirksamkeit der Intervention zu bestätigen.

4 laufende Studien

zu rTMS vs Sham

derzeit nicht erstattet

sehr niedrige Qualität

der Evidenz

methodische

Einschränkungen

QoL-Ergebnisse

und PatientInnen

Zufriedenheit in den

Studien vernachlässigt

rTMS ist sicher und gut

verträglich, effektiver

als Scheinintervention

Wirksamkeit gegenüber

ECT unklar

neue Studien mit

Langzeitdaten von rTMS

nötig um Wirksamkeit

zu bestätigen

(22)
(23)

Scope

LBI-HTA | 2017

21

1

Scope

1.1

PICO question

Is repetitive transcranial magnetic stimulation (rTMS) in patients with

treat-ment-resistant major depression as effective as or more effective than and as

safe as or safer than sham stimulation or electroconvulsive therapy (ECT)?

1.2

Inclusion criteria

Inclusion criteria for relevant studies are summarized in Table 1-1.

Table 1-1: Inclusion criteria

Description Project scope

Population

Adult patients (>18 yrs) with major depressive disorder (MDD) as defined by DSM IV-TR or ICD-10, which is treatment resistant (IV-TRD) and characterized by:

syndrome of unipolar depression with or without psychotic features and

lack of clinically meaningful improvement despite the use of at least 2 antidepressant agents from different pharmacological classes with each antidepressant medication trial being adequate in terms of dose, duration, compliance, and tolerability

Intended use of technology: third- and subsequent-line treatment

MeSH terms: Major depressive disorder F03.600.300.375, Depressive disorder, treatment-resistant: F03.600.300.387

ICD-10 categories: F32 Depressive episode, F33 Recurrent depressive disorder

Rationale: population has been chosen based on information from the relevant published clinical guidelines [5, 7, 20-24] and amended following comments from external experts.

Intervention

Repetitive transcranial magnetic stimulation (rTMS) as a therapeutic intervention in the acute phase

MeSH term: Transcranial Magnetic Stimulation E02.621.820

The following intervention will be considered:

High-frequency (≥5 Hz) rTMS of the left dorsolateral prefrontal cortex (DLPFC) as

monotherapy

or

add-on therapy

Products to be considered:

MagStim: Magstim Rapid2, Super Rapid2 and Super Rapid2 Plus1

Magventure: MagVita TMS Therapy system, Magpro X100 Stimulator, Magpro R30 Stimulator

Neurostar: NeuroStar TMS therapy system

Mag & More: PowerMAG, Different versions: PowerMAG Clinical 30, PowerMAG Clinical 100, PowerMAG Research 30, PowerMAG Research 100

Neurosoft: Neuro-MS, Neuro-MS/D

Rationale: relevant published clinical guidelines [5, 21] issued level A recommendation for the use of high-frequency rTMS of the left DLPFC; for the use of low-frequency rTMS of the right DLPFC level B recommendation (probable effect) has been issued.

PIKO-Frage

Einschlusskriterien

für relevante Studien

(24)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

22 LBI-HTA | 2017

Description Project scope

Comparison

Sham stimulation (with antidepressant medication or no medication)

ECT

Rationale: Comparator has been chosen based on information from EUnetHTA guidelines [25-27] and relevant published clinical guidelines [5, 7, 20-24], in which ECT is recommended for TRD patients after two treatment failures as a nonpharmacological treatment option. Other somatic therapies are not yet well established.

Outcomes

Clinical endpoints:

Clinical effectiveness

Change in depression score (measured on one of the following scales: HDRS/HAMD, MADRS, BDI or QIDS)

Response rate (≥ 50% reduction in the depression scores)

Remission rate (HAMD score <7, MADRS score <7, QUIDS score <5)

Patient satisfaction

QoL

Relapse rate

Safety:

Serious adverse device effect (SADE)

Seizure

Transient impairment of working memory

Induced currents in implanted devices

Adverse device effect (ADE):

Syncope (fainting)

Scalp discomfort or pain

Transient induction of hypomania

Transient hearing loss

Headache

Facial twitching

Vertigo

Device-related insomnia/drowsiness

Mild confusion

Other AEs

Rationale: outcomes have been chosen based on information from relevant published clinical guidelines [5, 7, 20-24] and EUnetHTA guidelines [25-27].

Abbreviations:

AEs adverse events, BDI Beck Depression Inventory, HDRS/HAMD Hamilton Depression Rating Scale, MADRS Montgomery-Asberg Depression Rating Scale, QIDS Quick Inventory of Depressive Symptomatology, QoL quality of life
(25)

LBI-HTA| 2017 23

2

Methods and evidence included

2.1

Research questions

Element ID Description and technical characteristics of the technology B0001 What are rTMS, sham stimulation and ECT?

A0020 For which indications rTMS received marketing authorisation or CE marking?

B0002 What is the claimed benefit of rTMS in relation to sham stimulation and ECT?

B0003 What is the phase of development and implementation of rTMS and ECT?

B0004 Who administers rTMS and ECT and in what context and level of care is it provided?

B0008 What kind of special premises are needed to use rTMS and ECT? B0009 What equipment and supplies are needed to use rTMS and ECT? A0021 What is the reimbursement status of rTMS?

Element ID Health problem and current use of the technology A0002 What is treatment-resistant major depressive disorder? A0003 What are the known risk factors for treatment-resistant major

depressive disorder?

A0004 What is the natural course of treatment-resistant major depressive disorder?

A0005 What are the symptoms and the burden of treatment-resistant major depressive disorder for the patient?

A0006 What are the consequences of treatment-resistant major depressive disorder for the society?

A0024 How is treatment-resistant major depressive disorder currently diagnosed according to published guidelines and in practice? A0025 How is treatment-resistant major depressive disorder currently

managed according to published guidelines and in practice? A0007 What is the target population in this assessment?

A0023 How many people belong to the target population? A0011 How much is rTMS utilised?

Element ID Clinical effectiveness

D0001 What is the expected beneficial effect of rTMS on mortality? D0005 How does rTMS affect symptoms and findings (severity,

frequency) of treatment-resistant major depressive disorder? D0006 How does rTMS affect progression (or recurrence) of

treatment-resistant major depressive disorder? D0011 What is the effect of rTMS on patients’ body functions? D0016 How does the use of rTMS affect activities of daily living? D0012 What is the effect of rTMS on generic health-related quality of life? D0013 What is the effect of rTMS on disease-specific quality of life? D0017 Were patients satisfied with rTMS?

(26)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

24 LBI-HTA | 2017

Element ID Safety

C0008 How safe is rTMS in relation to sham stimulation and ECT? C0002 Are the harms related to dosage or frequency of applying rTMS? C0005 What are the susceptible patient groups that are more likely

to be harmed through the use of rTMS?

C0007 Are rTMS, sham stimulation and ECT associated with user-dependent harms?

B0010 What kind of data/records and/or registry is needed to monitor the use of rTMS, sham stimulation and ECT?

2.2

Source of assessment elements

The selection of assessment elements is based on the HTA Core Model

Ap-plication for Rapid Relative Effectiveness (REA) Assessments (4.2). The

se-lected issues (generic questions) are translated into actual research questions

(answerable questions).

2.3

Search

Detailed tables on search strategy are included in

Appendix 1

.

Given the extensive body of evidence (randomized controlled trials/RCTs,

sys-tematic reviews/SRs and meta-analysis/MAs) the syssys-tematic literature search

and analysis of the studies was performed in two phases: secondary studies

(i.e. HTA reports and SRs) were screened as a first step and evaluated on the

basis of their scope, inclusion and exclusion criteria, and quality. Primary

studies were considered for inclusion in the second step. We did not apply

any restrictions on language.

The following sources of information were used in the first search:

Cochrane Library,

Centre for Research and Dissemination (CRD),

Embase,

Medline,

PsychInfo,

Handsearch (in reference list of relevant studies).

Secondary studies were retrieved in full-text version. HTA reports and SRs

were extracted and tabulated in ascending chronological order. Only the most

recent reports (published in 2012-2016) were discussed qualitatively. SRs were

assessed according to year of publication, time range, scope, and population

to identify the most recent review that overlapped with the scope of the

pre-sent assessment. The AMSTAR tool was used for quality assessment of SRs.

Details can be found in Table A-3 in Appendix 1. The Health Quality

Ontar-io (HQO) HTA report [13] was selected for update.

Bericht folgt

HTA Core Model für REA

Literatursuche in

2 Schritten:

1. Suche nach sekundär

Studien (HTA Berichte

und SR) in

5 Datenbanken

HTA Berichte und SRs

von 2012-2016

qualitative Bewertung

(27)

Methods and evidence included

LBI-HTA | 2017

25

To identify further, more recent, primary studies fulfilling the inclusion

cri-teria of the present assessment, a literature search for RCTs published since

the literature search of the chosen HTA report [13] was performed. The time

period of the search was limited to November 2014 to January 2017. The

fol-lowing sources of information were used:

Cochrane Library,

Embase,

Medline,

PsychInfo,

Handsearch (in reference list of relevant studies)

In addition, the following clinical trials databases were searched to identify

ongoing studies on the rTMS in major depression:

ClincalTrials.gov

EU Clinical Trials Register

International Clinical Trials Registry Platform (ICTRP).

Clinical Practice Guidelines (CPGs) were also searched in the UptoDate

da-tabase, through handsearch and consultation with clinical experts.

2. Suche nach

zusätzlichen primär

Studien (RCTs) in

4 Datenbanken

Suche nach laufenden

Studien zu rTMS

(28)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

26 LBI-HTA | 2017

2.4

Study selection

2.4.1

Selection of systematic reviews

Figure 2-1:

Flow chart for selection of systematic reviews

The author (LBI-HTA) and the co-author (OSTEBA) screened and selected

studies independently from each other. The author checked the

discrepan-cies. Any disagreements were resolved by consensus.

The search yielded 669 records and after deduplication, 326 records

re-mained for screening. The reference list was screened by title and abstract to

identify potentially relevant studies. A cross-reference search identified one

further study.

Literaturauswahl

insgesamt

326 Publikationen

identifiziert

Records identified through database searching (n = 669)

Scr

ee

ni

ng

Incl

ud

ed

E

lig

ib

ility

Id

en

tif

ic

atio

n

Additional records identified

through other sources (n = 1)

Records after duplicates removed (n = 327)

Records screened (n = 327)

Records excluded (n = 297) Full-text articles assessed

for eligibility (n = 30)

Full-text articles excluded, with reasons

(n = 10) Exclusion criteria are e.g.:

Background literature (n=4)

Other population (n = 0)

Not available (n = 3)

Other intervention (deep rTMS) (n = 2)

Not reporting the outcomes of interest (n = 1)

Studies included in qualitative synthesis (n = 20)

rTMS vs sham SRs (n = 9) rTMS vs ECT SRs (n = 6) rTMS vs sham and ECT SRs (n = 5)

Studies included in quantitative synthesis (n = 1)

(29)

Methods and evidence included

LBI-HTA | 2017

27

A total of 20 SRs were selected that fulfilled our inclusion criteria. 14 studies

had only one comparator each: nine compared rTMS with sham stimulation

and six compared active stimulation with ECT. Five SRs included both

com-parators. Seven SRs included various types of rTMS (HF, LF, mixed

frequen-cies) applied to different sites. From these we considered only the HF-rTMS

to the left DLPFC parts of the SR and extracted data regarding that

(num-ber of patients, studies included, scope of the assessment, inclusion criteria

used). We assessed the quality of the SRs with the AMSTAR tool. The HQO

report [13] was selected for update within the present assessment on the

ba-sis of the year of publication, time range, scope, population, intervention,

out-comes measured, comparators, and the AMSTAR score.

2.4.2

Selection of primary studies

Figure 2-2: Flow chart for selection of primary studies

20 SRs von denen

14 rTMS mit sham und

6 rTMS mit ECT, und

5 Studien beide

Interventionen mit

rTMS verglichen

Qualität mittels

AMSTAR bewertet

Records identified through database searching (n = 849)

Scr

ee

ni

ng

Incl

ud

ed

E

lig

ib

ility

Id

en

tif

ic

atio

n

Additional records identified

through other sources (n = 0)

Records after duplicates removed (n = 521)

Records screened (n = 521)

Records excluded (n = 505) Full-text articles assessed

for eligibility (n = 16)

Full-text articles excluded, with reasons

(n = 14) Exclusion criteria are e.g.:

Other intervention (maintenance therapy or targeting other than the left site) (n = 2)

Publication before the search period of interest (n = 9)

Study design non-RCT (n = 2)

Only follow-up data (n = 1) Studies included in qualitative synthesis

(n = 2) rTMS vs sham (n = 2)

rTMS vs ECT (n= 0)

Studies included in quantitative synthesis (n = 2)

(30)

Repetitive transcranial magnetic stimulation for treatment-resistant major depression

28 LBI-HTA | 2017

Primary studies in the period November 2014 – January 2017 were screened

to identify new evidence. The search yielded 849 records, after deduplication

521 records remained for screening. A hand search identified no further

stud-ies. In total, two studies [14, 15] were selected that fulfilled our inclusion

cri-teria and included within the present assessment. The two studies compared

HF-rTMS to the left DLPFC with sham. No studies were found that

com-pared active stimulation with ECT. Additionally, as the selected SR did not

define QoL as an efficacy outcome and the included primary studies did not

report on it, we also screened primary studies of the last 5 years (2012-2016).

We tried to find those studies that might have been excluded from the selected

SR in case they did not report on the primary outcomes defined in the SR.

2.4.3

Selection of guidelines

We identified guidelines via systematic search and hand search. The

guide-lines of the main scientific and professional organizations (APA, CANMAT,

IFCN, RAZCP, and WSFBP) and the guidelines applicable by professional

organizations of the author’s (Austria, DGPPN) and co-author’s (Spain,

AVALIA-t) country of origin were selected to be included in the overview of

available guidelines.

2.5

Quality rating of studies

AMSTAR was used to assess the quality of SRs and the Cochrane risk of bias

assessment approach was used to assess RCTs (ACROBAT-NRSi tool),

ac-cording to the EUnetHTA Guidelines on Therapeutic medical devices [25].

For the assessment of the strength of evidence, the “Grading of

Recommen-dations, Assessment, Development and Evaluation” – GRADE approach was

used. These steps were performed by the author independently from the

co-author(s). Any disagreements were resolved by consensus. The preliminary

classification of the importance of the outcomes (GRADE specifies three

cat-egories of outcomes according to their importance for decision-making:

cru-cial, important, and of limited importance) was done in consensus by the

au-thors.

For Description and Technical Characteristics of Technology (TEC) and

Health Problem and Current Use of the Technology (CUR) domains, no

qual-ity assessment tool was used, but multiple sources were used in order to

val-idate individual, possibly biased, sources. Descriptive analysis of different

information sources was performed. The completed EUnetHTA submission

file from the manufacturers was used as a starting point. The AGREE II tool

was used for the quality rating of guidelines. Two authors scored the

guide-lines independently from each other, disagreements were solved by consensus.

insgesamt

521 Primärstudien

identifiziert

Leitlinien relevanter

Organisationen,

im besonderen aus

Österreich und Spanien

AMSTAR zur Bewertung

der Qualität der

sekundär Studien

Zusammenfassung der

Ergebnisse mit GRADE

AGREE II zur

Bewertung der

Qualität der Leitlinien

(31)

Methods and evidence included

LBI-HTA | 2017

29

2.6

Statistical-analysis

We conducted a meta-analysis of the pooled results in the R environment [28]

using the package ‘‘meta’’ [29]. The HQO report used a random effects model

for the meta-analysis; we also chose this model in our calculations. The degree

of statistical heterogeneity among studies was assessed using the I-squared

(I

2

) and tau-squared statistics.

We calculated changes in depression scores measured by Hamilton Rating

Scale for Depression from baseline to the end of treatment and conducted a

meta-analysis on the mean changes in scores for the rTMS treatment and

con-trol groups. We calculated the effect size as the difference between the means

of the two groups divided by the standard deviation (SD), a statistical

meth-od known as standardized mean difference (SMD) using Cohen’s methmeth-od.

We used Cohen’s conventional definition of small, medium, and large effect

size as 0.2, 0.5, and 0.8, respectively. Pooled effect sizes for depression scores

were calculated in the HQO report using weighted mean difference, the mean

difference value of 3.5 points on the Hamilton Rating Scale for Dep

References

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